Pancreatic Adenocarcinoma Cell Lines Show Variable Susceptibility to TRAIL-Mediated Cell Death

Ibrahim, Saleh M.; Ringel, Jörg; Schmidt, Christian; Ringel, Bruno; Müller, Petra; Koczan, Dirk; Thiesen, Hans‐Jürgen; Löhr, Matthias

doi:10.1097/00006676-200107000-00011

Cited by 79 publications

(54 citation statements)

References 55 publications

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“…These include mutations in the death receptor genes 18 and overexpression of inhibitory molecules such as soluble death receptors, 19 decoy receptors 20 and FLIP. 21 In addition, epigenetic silencing of members of the death receptor pathway via DNA methylation can also occur.…”

Section: Discussionmentioning

confidence: 99%

Silencing of death receptor and caspase-8 expression in small cell lung carcinoma cell lines and tumors by DNA methylation

et al. 2003

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Small cell lung cancer cell lines were resistant to FasL and TRAIL-induced apoptosis, which could be explained by an absence of Fas and TRAIL-R1 mRNA expression and a deficiency of surface TRAIL-R2 protein. In addition, caspase-8 expression was absent, whereas FADD, FLIP and caspases-3, -7, -9 and -10 could be detected. Analysis of SCLC tumors revealed reduced levels of Fas, TRAIL-R1 and caspase-8 mRNA compared to non-small cell lung cancer (NSCLC) tumors. Methylation-specific PCR demonstrated methylation of CpG islands of the Fas, TRAIL-R1 and caspase-8 genes in SCLC cell lines and tumor samples, whereas NSCLC samples were not methylated. Cotreatment of SCLC cells with the demethylating agent 5 0 -aza-2-deoxycytidine and IFNc partially restored Fas, TRAIL-R1 and caspase-8 expression and increased sensitivity to FasL and TRAIL-induced death. These results suggest that SCLC cells are highly resistant to apoptosis mediated by death receptors and that this resistance can be reduced by a combination of demethylation and treatment with IFNc.

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Section: Discussionmentioning

confidence: 99%

Silencing of death receptor and caspase-8 expression in small cell lung carcinoma cell lines and tumors by DNA methylation

et al. 2003

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“…In breast cancer cells, the treatment of 2-ME caused cell cycle dependent alteration in the level of cyclic-AMP accompanied by changes in the phosphorylation pattern of various proteins (Lottering et al, 1996). 2-ME is also known to up regulate DR5 (death receptor) and sensitizes cells to TRAIL induced apoptosis (Ibrahim et al, 2001). Furthermore, similar to other microtubule inhibitors, 2-ME treatment can trigger Bcl2 phosphorylation and apoptosis in erythromyeloid K562 cells (Attala et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

2-Methoxyestradiol induces mitochondria dependent apoptotic signaling in pancreatic cancer cells

et al. 2002

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“…However, most pancreatic adenocarcinoma cell lines are resistant to death receptor-and mitochondria-initiated apoptosis (2,13).…”

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confidence: 99%

Somatostatin receptor subtype 2 sensitizes human pancreatic cancer cells to death ligand-induced apoptosis

Guillermet

Saint-Laurent

Rochaix

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

118

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Somatostatin receptor subtype 2 (sst2) gene expression is lost in 90% of human pancreatic adenocarcinomas. We previously demonstrated that stable sst2 transfection of human pancreatic BxPC-3 cells, which do not endogenously express sst2, inhibits cell proliferation, tumorigenicity, and metastasis. These sst2 effects occur as a consequence of an autocrine sst2-dependent loop, whereby sst2 induces expression of its own ligand, somatostatin. Here we investigated whether sst2 induces apoptosis in sst2-transfected BxPC-3 cells. Expression of sst2 induced a 4.4-؎ 0.05-fold stimulation of apoptosis in BxPC-3 through the activation of tyrosine phosphatase SHP-1. sst2 also sensitized these cells to apoptosis induced by tumor necrosis factor ␣ (TNF␣), enhancing it 4.1-؎ 1.5-fold. Apoptosis in BxPC-3 cells mediated by TNF-related apoptosis-inducing ligand (TRAIL) and CD95L was likewise increased 2.3-؎ 0.5-fold and 7.4-؎ 2.5-fold, respectively. sst2-dependent activation and cell sensitization to death ligand-induced apoptosis involved activation of the executioner caspases, key factors in both death ligand-or mitochondria-mediated apoptosis. sst2 affected both pathways: first, by up-regulating expression of TRAIL and TNF␣ receptors, DR4 and TNFRI, respectively, and sensitizing the cells to death ligand-induced initiator capase-8 activation, and, second, by down-regulating expression of the antiapoptotic mitochondrial Bcl-2 protein. These results are of interest for the clinical management of chemoresistant pancreatic adenocarcinoma by using a combined gene therapy based on the cotransfer of genes for both the sst2 and a nontoxic death ligand.

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Pancreatic Adenocarcinoma Cell Lines Show Variable Susceptibility to TRAIL-Mediated Cell Death

Cited by 79 publications

References 55 publications

Silencing of death receptor and caspase-8 expression in small cell lung carcinoma cell lines and tumors by DNA methylation

Silencing of death receptor and caspase-8 expression in small cell lung carcinoma cell lines and tumors by DNA methylation

2-Methoxyestradiol induces mitochondria dependent apoptotic signaling in pancreatic cancer cells

Somatostatin receptor subtype 2 sensitizes human pancreatic cancer cells to death ligand-induced apoptosis

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